Myopia (short-sightedness) results from a failure of emmetropization in which eyes grow too long for their optical power. Myopia's association with sight-threatening complications and near-epidemic prevalence in several populations make it critical that effective treatments for slowing myopia progression be developed. The chick eye has provided a very fruitful model, yielding evidence for local retinal control of eye growth, identifying multifocal (MF) optical manipulations that inhibit ocular elongation as potential myopia treatments, and providing initial insights into the mechanism underlying atropine's anti-myopia action. The guinea pig, a mammalian model with a fibrous sclera more like human sclera, has yielded valuable translational data. Our proposal relied on recent findings from many labs, including our own, to develop a multi-pronged approach to myopia control. It exploits novel tools and advanced technologies to pursue 4 aims: (1) We will use our novel optical imaging (cone) devices and MF spectacle lenses combined with neurotoxins to further investigate the mechanisms underlying MF lens effects on eye growth, and the variables influencing treatment efficacy. (2) We will investigate the anti-myopia actions of atropine, to better understand the roles of retinal and nonretinal mechanisms and to determine effective dosing regimens. (3) We will investigate whether treatment efficacy can be improved by combining MF lenses designed to slow myopic growth with either or both atropine and very bright light, which is also known to slow myopia progression. Experiments under Aim 3 will make use of results from earlier experiments (Aims 1 & 2). We will apply molecular biology tools to study retinal/retinal pigment epithelium (RPE) signal pathways. RPE gene expression signatures of myopic and hyperopic growth developed in the last grant period will be exploited to obtain insights into nature of treatment mechanisms and interactions. (4) We will test MF contact lenses in guinea pig to translate our recent related MF spectacle lens studies and look for parallels with chick retinal and RPE molecular signatures that may be applied to understand ocular growth signals.